PROJECT DESCRIPTION / ABSTRACT In addition to infections, gut commensal microbes influence the pathogenesis of autoimmune diseases. Bacteroides fragilis is a gram-negative anaerobe and an integral component of the human gut symbiotic microflora. However, this is also the most commonly isolated organism from clinical cases of intra-abdominal abscess. Recent studies have used B. fragilis as a model for studying the commensal bacteria-human host interactions. Using experimental models, studies have demonstrated many beneficial effects of B. fragilis and its major capsular component, polysaccharide A (PSA) including enhancement of gut and systemic immune regulation through activating regulatory T cells under normal circumstances. However, employing this organism and autoimmune susceptible mice as models, we observed that gut commensal microbes can produce deleterious effects upon gaining access to systemic circulation. While orally administered, heat-killed B. fragilis caused protection from spontaneous autoimmune diabetes, i.v. administration of small amounts of this bacterium led to rapid onset of the disease. These observations suggest that systemic exposure to this, and perhaps other similar, commensal bacteria due to transient or persistent enhanced gut permeability could trigger or accelerate autoimmunity in individuals who are genetically susceptible to the disease. Therefore, in this proposed work, we will determine if systemic exposure to B. fragilis due to compromised epithelial barrier function impacts autoimmune outcome, using spontaneous mouse model of type 1 diabetes (T1D) in specific pathogen free (SPF) and germ-free (GF) backgrounds. We will also ask if a well-recognized symbiotic factor of B. fragilis, PSA and its interaction with toll- like receptor 2 contributes to these paradoxical autoimmune outcomes. Further, employing high dimensional and high throughput approaches, we will assess if PSA-specific response to B. fragilis by systemic and intestinal immune cells are significantly different. We believe that results from these novel exploratory studies will shed light on the contribution of interaction between commensal bacteria and gut mucosa to autoimmunity in genetically susceptible subjects.